For the growth of malignant tumors, oxygen and nutrition are necessary. Malignant tumors therefore secrete a vascular endothelial growth factor (VEGF) and the like to cause angiogenesis for themselves. Inhibition of angiogenesis is presumed to suppress growth or malignant transformation of tumors so that there have been proposed various molecular targeting therapies with VEGF or VEGFR2, a receptor of vascular endothelial growth factor, as a target.
VEGFR2 is composed of an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain and it interacts with VEGF through the extracellular domain. VEGFR2, when a dimer VEGF binds thereto, dimerizes and is activated through auto-phosphorylation by the intracellular tyrosine kinase domain. The activation of VEGFR2 causes migration, growth, and survival of cells, resulting in angiogenesis. Inhibition of interaction between VEGF and VEGFR2 or signaling caused thereby is presumed to be clinically useful because it can suppress pathological angiogenesis such as retinal angiopathy as well as malignant tumors (refer to, for example, Non-patent Documents 1 to 4).
In practice, anti-VEGF neutralizing antibodies, anti-VEGFR2 neutralizing antibodies, and compounds inhibiting VEGFR2 phosphorylation have been under development and some of them have already been industrialized (refer to the above-mentioned Non-patent Document 1). Anti-VEGF antibodies have been verified to exhibit a certain effect when used in combination with chemotherapy; however, they are expensive and are required to have a low molecular weight. A small-molecule inhibitor against phosphorylation of VEGFR2 has already been developed, but it still has a problem in specificity.